Synthesis of corticosterone



Patented Feb. 8, 1944 UNITED STATES PATENT OFFICE SYNTHESIS OF CORTICOSTERONE Everett S. Wallis and Pumemlu nath Chakravorty, Princeton, N. J., assignors to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application February 5, 1940, Serial No. 317,418

13 Claims. (Cl.

OH CH1: 0

The conversion of this desoxycholic acid into a desirable intermediate in the direction of corticosterone synthesis involves the two problems of substituting the OH group in the C12 position of the desoxycholic acid by hydrogen and introduci ing a double bond at the 0 9-11 position which 40 double bond may then be converted by suitable methods to the corresponding saturated C11 oxylated compound. The desoxycholic acid is oxidized directly to 3-hydroxy-l2-ketocholanic acid by the method described by Kaziro and Shimada, i. e. by the action of a solution of chromic oxide 7 in acetic acid containing 7% of water, the reaction mixture being maintained at a temperature of 0 C. to 5 C. The 3-h'ydroxy-12-ketocholanic acid is obtained in good yields and is readily separated and purified by conventional methods. The methyl ester of this acid melts at 143 C. The 3-hydroxy-12-ketocholanic acid is acetylated (the acetoxy derivative melts at 197 C.) and then brominated by treatment with bromine in either chloroform or acetic acid solution in the presence of hydrogen bromide at 70 C. yielding B-acetoxy-11-bromo-l2-ket0cholanic acid. This bromide is a white crystalline solid having a melting point of 184 C. This compound is dehydrohalogenated, introducing the double bond, by treatment with sodium ethylate in absolute alcohol at water bath temperature for /2 hour and yields a white crystalline solid, 3-hydroxy- 12-keto-9:ll-cholenic acid, having a melting point of 1'72-1'l3 0. Its acetate melts at 199 C.

It is of interest to note at this point that dehydrohalogenation by means of zinc and acetic acid yields the saturated 3-hydroxy-12-ketocholanic acid and also that dehydrohalogenation with sodium acetate and acetic acid failed to give the desired product.

The above product, 3-hydroxy-12-keto-911lcholenic acid, is treated with an alcohol solution of semicarbazide acetate or semicarbazide hydrochloride with sodium acetate to produce the semicarbazone having a melting point of 221 C. The semicarbazone is reduced by heating with sodium ethylate in a sealed tube at 180 C. for 15 hours yielding the corresponding methylenic compound in readily crystallizable form. It is mixture is then cooled with ice water and to it contaminated, as would be expected, withasmall is added an ice cold solution of 20% sulfuric amount of its epimer, B3-hydroxy-9zll-cholenic acid. After standing in the ice box for one half acid b t is latter p u d is removed by hour the precipitated acid so obtained is filtered y alliz t fr m a -3- y r xy-9zll- .5 and washed free from sulfuric acid. It is then cholenic acid crystallizes in needles from acetone taken up in ether and the dried ether solution and melts at 183-184" C. Its acetate melts at decolorized with charcoal. The solution is then 165 C. concentrated to a small volume and allowed to Furth r d tai s of the p s up to this oint stand. (If the ether solution is perfectly dry are given y h f ll wing r i n quations: 10 and if the removal of hydrogen bromide has CH3 H3 0 H3 CHCH2CHa-COOH 0 CH3 CH-CH2CH2000H acetylation followed by I I bromination Bra in CHCl;

or acetic acid, presence of HBr at 70 C.

CrOa in acetic aciitilt (6135 1589) H0\/ Desoxycholic acid 3-hydroxy-l2-ketocho1anic acid CH CH3 CH3 CH-CHzCHzCOOH 0 CH: CHCH2CH2COOH sodium ethylate and i alcohol solution of semiabsolute alcohol carbazide HCl+sodium water bath temp. acetate refluxed 1 hour AcO V [or 36 hour HOk/ converted to semicarbazone 3-acetoxy-ll-bromo-l2-ketocholanic acid 3-hydr6xy-l2-keto-9:ll-cholenic acid H on; OH; HzN-O-N-N ll 0H1 H-OHzCHzCOOH on, H-CH1CHr-COOH O CH: 1 011a:

treat with anhydrous sodium ethylate in B0 a e? 22 1. r HOL 01 OUTS Scmicarbazone of 3-l1ydr0xy-l2- B-hydroxy-Qzll-cliolenic acid keto-Qzll-cholenic acid The step of bromi'nating the 3-acetoxy-l2-ketobeen complete, crystallization of the dissolved cholanic acid may be carried out by dissolving acid begins when the solution has reached about grams of this acid in cc. of glacial acetic half its original volume.) The crystalline prodacid and adding 15 cc. of a 1.05 N acetic acid 'uct so obtained is filtered and washed with cold solution of bromine. A few drops of a 34% aqueether. A sample of it melted at 160-165 C. Reous solution of hydrogen bromide are added'as crystallization from ethyl acetate gives a prodcatalyst. The solution is kept at 70 C. for 4 uct which melted at 172-173" C. Its acetate melts hours and then allowed to stand over night at at 199 C.

room temperature. It is then poured into ice 5 For the conversion of the 3-hydroxy-12-ketowater and the amorphous powder which precipi- 9:11 cholenic acid described above into the 3- tates is separated by filtering. After thorough hydroxy-Qzll cholenic acid the following prowashing with water it is dissolved in ether and cedure may be employed. A portion of the acid the ether solution washed to remove hydrogen (0.2 g.) is refluxed for two hours with an aqueous bromide. After drying with NazSO4 the ether alcoholic solution of 0.2 g. semicarbazide acetate is evaporated to dryness and the bromide obprepared from semicarbazide hydrochloride and tainedas a sticky reddish residue. 0.2 g. of anhydrous sodium acetate. The product In the next step of the process, i. e. the deis worked up in the usual manner. From benhydrohalogenation, this residue is taken up in abzene it comes down as a gelatinous precipitate solute alcohol and poured into a hot solution of oiwhich becomes crystalline when filtered and sodium ethylate (prepared from 6 g. of sodium washed with ether. The crystals melt at 221 C.

dissolved in cc. absolute alcohol). Imme- The semicarbazone is not further purified but is diately the mixture becomes very dark brown directly employed for the Wolf-Kishner reducand some sodium bromide precipitates. Heating tion. The heating with sodium ethylate (made is continued for two hours after which time a 70 from 1 gasodium and 15 cc. of absolute alcohol) considerable amount of sodium bromide has preis carried out in a sealed tube at 180 C. for fifcipitated. The condenser is then removed and teen hours. After this time the reaction product after suiiicient water has been added to dissolve is taken up in water and boiled for one half hour the salt the boiling is continued to remove as on the water bath. After cooling with ice it is much of the alcohol as possible. The reaction acidified with ice cold dilute sulfuric acid. The

precipitate so obtained is filtered, washed thor oughly with water and then taken up in acetone. On crystallization needles are obtained which melt unsharply at 175 C. 'Several recrystallizations from acetone give a product which shows a strong positive Liebermann reaction and which melts at 183-18 C. The 3-hydroxy-9zll cholenic acid may be acylated by conventional procedure to yield the 3-acetoxy-9zll cholenic acid.

We claim:

1.- Process which comprises oxidizing desoxycholic acid to 3-hydroxy-12-ketocholanic acid, acetylating and then brominating the latter to 3- acetoxy-ll-bromo-lZ-ketocholanic acid, converting the latter to 3-hydroxy-l2-keto-9:ll-cholenic acid by treatment with sodium ethylate; converting the 3-hydroxy-12-keto-9:ll-cholenic acid to the corresponding 12-semicarbaz0ne by treatment thereof with semicarbazide acetate, reducing the resulting IZ-semicarbazone compound to 3-hydroxy-9:11-cholenic acid by treatment with sodium ethylate and acetylating the product to the 3-acetoxy-9z1l-cho1enic acid.

2. Process which comprises oxidizing desoxycholic acid to 3-hydroxy-12-ketocholanic acid, acylating the S-hydroxy-12-ketocholanic acid to 3-acyloxy-12-ketocholanic acid, halogenating the 3-acy1oxy-12-ketocholanic acid to 3-acyloxy-11- halogeno-12-ketocholanic acid, dehydrohalogenating the latter compound by means of an alkali metal alkylate' to the production of 3-hydroxy- 12-keto-9z11-cholenic acid, forming the l2-semicarbazone of the latter compound, and reducing the semicarbazone compound to 3-hydroxy-9:11- cholenic acid.

3. Process which comprises oxidizing desoxycholic acid to 3-hydroxy-12-ketocholanic acid, acetylating the 3-hydroxy-12-ketocholanic acid to 3-acetoxy-12-ketocholanic acid, and brominating the 3-acetoxy-l2-ketocholanic acid to 3- acetoxy-ll-bromo-lZ-ketocholanic acid.

4. Process which comprises oxidizing desoXycholic acid to B-hydroxy-lz-ketocholanic acid, acetylating the 3-hydr0xy-l2-ketocholanic acid to 3-acetoxy-12-ketocholanic acid, brominating the 3-acetoxy-IZ-ketocholanic acid to 3-acetoxy- 1l-bromo-lZ-ketocholanic acid and dehydrobrominating the latter compound by means of an alkali metal alkylate to the production of 3- hydroxy-lZ-keto-Q ll-cholenic acid.

5. Process which comprises dehydrobrominating 3-acetoxy-1l-bromo-12-ketocholanic acid by a treatment with sodium ethylate in absolute alcohol, at water bath temperature, to the production of 3-hydroxy-12-keto-9:ll-cholenic acid.

6. Process which comprises treating 3-hydroxy-l2-keto-9:ll-cholenic acid with semicarbazide acetate, to the production of 3-hydroxy- 12-semicarbazone-9:ll-cholenic acid, and reducing the resulting semicarbazone compound by heating the same with sodium etl'iylate, to the production of B-hydroxy-Szll-cholenic acid.

7. A method of converting a 12-hydroxy compound containing the grouping to the corresponding 9:11 unsaturated-12- desoxy compound which comprises oxidizing the 12-hydroxy compound to the corresponding 12- keto compound, halogenating the 12-keto compound to the corresponding alpha-halogeno compound, eliminating hydrogen halogenide from the alpha-halogeno compound to form the corresponding alpha-beta unsaturated keto compound; forming the semicarbazone of the alphabeta unsaturated keto compound, and reducing the semicarbazone to the corresponding 9: 11 unsaturated-IZ-desoxy compound.

8. A method of converting a 3:12-dihydroxy compound containing the grouping to the corresponding 9:11 unsaturated-12- desoxy compound which comprises oxidizing the 3,12 dihydroxy compound to the corresponding 3 hydroxy-lZ-keto compound; converting the 3 hydroxy-l2-keto compound to the corresponding alpha-halogeno compound by halogenation after previously protecting the hydroxyl group in the 3-position by acylation; converting the alphahalogeno compound thus formed to the corre sponding alpha-beta unsaturated keto compound by treatment with an alkali metal alkylate in absolute alcohol; converting the alpha-beta unsaturated keto compound thus formed into the corresponding semicarbazone by treatment with an alcoholic solution of semicarbazide-HCI in the presence of an alkali metal acylate; converting the semicarbazone of the alpha-beta unsaturated keto compound thus formed into the corresponding 9:11 unsaturated-IZ-desoxy compound by treatment with anhydrous alkali metal alkylate, and converting the 9: 11 unsaturated 12- desoxy compound into the corresponding acyloxy derivative.

9. Process which comprises halogenating a 3- acyloxy-lZ-keto cholanic acid to the corresponding 3-acyloxy-l1-halogeno 12 keto cholanic acid, dehydrohalogenating the latter compound by means of an alkali metal alkylate to the production of 3-hydroxy-12-keto 9:11 cholenic acid, forming the 12-semicarbazone of the latter compound, and reducing the semicarbazone compound to 3-hydroxy-9:11-cholenic acid.

10. Process which comprises halogenating a 3- acyloxy-12-keto-cholanic acid to the corresponding 3-acyloxy-ll-halogeno-lZ-keto cholanic acid.

11. Process which comprises halogenating a 3- acyloxy-12-keto-cholanic acid to the corresponding 3-acyloxy-ll-halogeno 12 keto cholanic acid, and dehydrohalogenating the latter compound by means of an alkali metal alkylate to the production of 3-hydroxy-12-keto-9:ll-cholenic acid.

12. A compound of the formula in which R stands fora member of the group con- CHB sisting of hydrogen and acyl.

I 13. Process as defined in claim 4 in which the CH5 CH' CF9 CHCOOH 3-hydroxy-12-keto-9:ll-cholenic acid is con- 5 verted to the corresponding 12-semicarbazone by 1 treatment thereof with semicarbazide acetate [1 i and the resulting lz-semicarbazone compound is reduced to 3-hydroxy-9z11-cho1enic acid by treatment with sodium ethylate. I I EVERETT S. WALLIS. 0 PURNENDU mm CHAKRAVORTY. 

